StarCraft II features the return of the three species from the original game: Protoss, Terran, and Zerg.In the Terran campaign, the original StarCraft briefing room is replaced with an interactive version of the battlecruiser Hyperion, with Jim Raynor, now a bitter and hard-drinking mercenary captain, as the central character. In a departure from previous Blizzard games, the campaign is non-linear, with Raynor taking jobs for money and using that money to buy additional units and upgrades. Although each playthrough will vary, the end result remains consistent, keeping the storyline linear. Vice President Rob Pardo stressed that each campaign will function very differently. The Terran campaign, Wings of Liberty, places players in a mercenary-style campaign, as Terran rebel Jim Raynor performs missions for cash.

The second release, the Zerg campaign Heart of the Swarm, will have role-playing elements. The player will level up the Queen of Blades, Kerrigan, throughout the missions. In the last expansion, the Protoss campaign Legacy of the Void, the dark templar Zeratul will have to employ diplomacy between Protoss tribes to acquire units and technologies for each mission. Each campaign is expected to span 26–30 missions. Wings of Liberty has 29 playable campaign missions, but only 26 of them are playable in a single playthrough since three missions are choice-related alternates. There is one secret mission named "Piercing the Shroud", which can be unlocked on the "Media Blitz" mission.